Aggressive subtype of breast cancer displays ’misbehavior’ of X chromosomes

Basal-like breast cancers (BLC) are highly aggressive tumors with a relatively poor prognosis that account for approximately 15% of sporadic human breast cancer. Sporadic BLC share certain characteristics with most of the breast cancers from patients carrying a germline mutation in the BRCA1 breast cancer suppressor gene. Among their similarities, sporadic BLC and BRCA1 cancers do not express the estrogen receptor and do not overproduce HER2 protein. Thus, therapeutics targeting estrogen receptor or targeting HER2 currently used in treating some other types of breast cancers are unlikely to be useful for treating these breast cancers. However, sporadic BLC contain normal BRCA1 genes. A new study published in the February issue of Cancer Cell provides evidence that X chromosome abnormalities contribute to the pathogenesis of both the sporadic BRCA1 normal BLC and the inherited BRCA1 mutant breast cancer.

Defects in the BRCA1 gene have been linked to an abnormality in a mechanism that contributes to the stability of sex chromosomes in women. In mammals, male cells contain an X and a Y chromosome, while female cells contain two X chromosomes. Normally, a process called X inactivation occurs in early female embryos; it leads to silencing of one of the two X chromosomes in derivative embryonic and adult somatic cells. The authors had previously shown that loss of the inactive X chromosome (Xi) occurs in BRCA1 mutation-carrying breast cancers. Given the similarities between BRCA1-associated cancer and sporadic BLC, Drs. Andrea Richardson, Zhigang Wang, Dirk Iglehart, David M. Livingston, and Shridar Ganesan, and colleagues from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, examined whether sporadic BLC display abnormalities in the management of the Xi chromosome.

The researchers found that, like BRCA1-associated cancers, most sporadic BLC have consistently lost the Xi and displayed a higher than normal number of apparently active X chromosomes These tumors also showed increased expression of a small, but specific, subset of X chromosomal genes. Interestingly, since all sporadic BLC analyzed displayed normal BRCA1 genes and gene expression, it was hypothesized that BLC have acquired defects in genes other than BRCA1 that contribute to some of the same cellular pathways as those that are defective in BRCA1-associated cancers. One wonders whether one or more of these pathways support(s) the maintenance of a normal Xi. “These results provide new insight into possible pathogenic mechanisms underlying both sporadic and BRCA1-associated basal-like breast cancer,” explain the authors. Ideally, a better understanding of how two active X chromosomes are associated with cancer development and progression could lead to new insights into rational treatment strategies for these subtypes of breast cancer.